Adolescence is a critical developmental period during which alcohol use is often initiated. In addition to the detrimental effects that alcohol exposure can have on the brain during this sensitive developmental period, adolescent alcohol use is also associated with increased risk of dependence in adulthood. Thus, understanding the mechanisms underlying adolescent drinking is critical. A possible behavioral mechanism for increased alcohol drinking during adolescence and later in adulthood is diminished sensitivity to the interoceptive effects of alcohol. All drugs of abuse share the common attribute that they produce interoceptive/subjective effects in humans and animals, and these interoceptive effects are a major controlling process of drug seeking behavior and abuse liability. The interoceptive effects of alcohol and other drugs are routinely measured in animals using operant drug discrimination methods, in which animals are trained to discriminate between drug and non-drug interoceptive cues. To date, the alcohol and drug abuse field has not had the appropriate tools by which to adequately evaluate drug interoceptive effects during the brief adolescent period in rodents. This is due, in part, to the lengthy training procedures required in operant drug discrimination techniques. As such, little is known about interoceptive drug effects in adolescence. To address this gap in knowledge, the studies in this proposal incorporate a Pavlovian discrimination training method. This procedure is ideal for assessment of the interoceptive effects of alcohol within a short developmental window because as we show in Preliminary Studies, the rats quickly acquire the discrimination in a time frame that spans the adolescent developmental period. The studies in this application have two separate but integrated Specific Aims.
In Specific Aim 1, experiments assess sensitivity to the interoceptive effects of alcohol in adolescents using the Pavlovian discrimination procedure. Adolescence is a critical period during which GABAergic and NMDA receptor systems undergo neurochemical remodeling and maturation. Interestingly, these systems are known to be major components of the alcohol drug cue (in adults) using operant discrimination techniques. Therefore, experiments will determine mechanistic involvement of GABAA and NMDA receptor-related systems underlying differential sensitivity to alcohol. The information gained from these studies could suggest a behavioral mechanism for increased alcohol drinking by adolescents. That is, adolescents may drink more alcohol because they are less sensitive to the interoceptive effects of the consumed alcohol. Further, given that interoceptive drug effects are a primary determinant of abuse liability, it is possible that experiencing the effects of alcohol during adolescence alters the perception of the alcohol cue in adulthood. Accordingly, another advantage of the Pavlovian discrimination procedure is that direct comparison between sensitivity to alcohol in adolescence and later in adulthood can be made. Thus, in Specific Aim 2, experiments will examine whether sensitivity to the alcohol cue in adulthood is altered after experiencing alcohol in adolescence. Further, given the developmental changes in GABAergic and glutamatergic mechanisms during adolescence the underlying mechanism (GABA or NMDA-related systems) will also be examined. Together, the exploratory and highly novel studies in this proposal, that incorporate a training method that has not been utilized to examine the interoceptive effects of alcohol, aim to extend our understanding of the interoceptive effects of alcohol in adolescence, and potentially contribute a behavioral mechanism that can inform our understanding of alcohol drinking in adolescence and increased risk for alcohol use in adulthood.

Public Health Relevance

Adolescence is critical developmental period during which alcohol use is often initiated. In addition to the detrimental effects that alcohol exposure can have on the brain during this sensitive developmental period, adolescent alcohol use is also associated with increased risk of dependence in adulthood. Thus, understanding the mechanisms underlying adolescent drinking is critical. A possible behavioral mechanism for increased alcohol drinking in adolescence is decreased sensitivity to the interoceptive/subjective effects of alcohol during the adolescent period. Therefore, the purpose of this application is to utilize a novel behavioral training tool by which to examine whether adolescents are differentially sensitive to the interoceptive effects of alcohol and whether that alcohol interoceptive cue is les salient in adulthood.